Project Summary Bladder nociceptive afferents play an important role in painful bladder syndrome/interstitial cystitis (PBS/IC). Although extensive research has been conducted to understand the involvement of parasympathetic pelvic C- fiber afferents in bladder nociception, very few studies have investigated the role of sympathetic hypogastric afferents. Previous animal studies have shown that sympathetic hypogastric afferents respond to bladder distension and/or irritation. Clinical evidence also supports the role of sympathetic afferents in bladder sensation/pain because blockade of the sympathetic afferent pathway can significantly relieve visceral pelvic pain including PBS/IC symptoms and bladder sensation/pain can still be elicited in human subjects with destroyed sacral spinal cord or transected sacral spinal roots. Since both sympathetic hypogastric nerves and parasympathetic pelvic nerves innervate the bladder, bladder distention/irritation always activates both pathways, causing significant difficulty in separating the functions of these two pathways in bladder nociception. Currently it is still unknown how sympathetic hypogastric afferents interact with the parasympathetic pelvic afferents in the CNS to modulate bladder function. It is also unknown if sympathetic hypogastric afferents alone can trigger bladder reflex activity and what role the sympathetic hypogastric nociceptive afferents play in bladder nociception/overactivity. Without this basic knowledge, our understanding of bladder nociception is certainly incomplete, which is evident clinically when diagnosing and attempting to treat PBS/IC. Therefore, in this grant application we propose to determine the functions of both parasympathetic nociceptive pelvic C-fiber afferents and sympathetic nociceptive/non-nociceptive hypogastric afferents in the control of bladder reflex activity and to determine the central convergence/interaction between sympathetic hypogastric afferents and parasympathetic pelvic nociceptive/non-nociceptive afferents. The success of our project will provide the basic scientific knowledge of bladder nociception and will benefit millions of Americans suffering from PBS/IC.